Acute kidney injury (AKI) leads to a sudden impairment of renal function. The effects of AKI may be transient followed by full or partial recovery, but often progress to more severe renal insufficiency or end-stage renal disease. There are no approved therapies available. Previous studies support the view that, at sufficiently high doses, recombinant human (rh) erythropoietin (EPO) protects kidneys in animal models of AKI. However, high doses are needed to achieve renal protection in preclinical studies, 5,000 IU/kg daily, because rhEPO does not efficiently access the extravascular system. The currently recommended doses of rhEPO in clinical settings are far lower (maximum to 900 IU/kg weekly), suggesting that dosing rhEPO at levels required to provide renal protection are not therapeutically viable. Consistent with this notion, the first clinical studies testing rhEPO in AK have provided mixed results, supporting the conclusion that more effective therapies are needed. RhEPO also associates with adverse effects due to its erythropoietic activity increasing the risk of thrombotic events. STATegics is focused on the discovery and development of small molecule cytokine mimetics and has identified non-erythropoietic EPO receptor (EPOR) agonists with potent tissue-protective activity. Using the human proximal tubule cell line HK-2, we find that these compounds activate EPOR and improve survival of the kidney cells in vitro. In addition, our studies indicate protective effects of the compounds on kidney function following chemically-induced AKI in vivo. Potent cytoprotective effects were also observed in rat and human neurons, illustrating broadly protective effects of these small molecules against cytotoxic challenges. In vitro safety assessment did not identify any safety concerns or off-target effects, and the compounds were well tolerated in an initial tolerability study in vivo. Importantly, no erythropoietic activity was observed at cytoprotective concentrations, in vitro or in vivo, suggesting a reduced risk of thrombotic events in vivo when compared to rhEPO. This Phase I program aims to establish a proof-of-concept for tissue- protective, non-erythropoietic small molecule erythropoietin EPOR agonists as potential disease-modifying agents in the treatment of AKI. The aim of the proposed studies is to evaluate and rank the protective effects of two promising compounds in this series using primary human and rat kidney cells in vitro and to test the ability of the most promising compound to protect rats from cisplatin-induced AKI in vivo. If the compound's kidney protective effects can be confirmed, our aim will be to expand into additional models of kidney injury, such as ischemia-reperfusion models. The latter studies would be the subject of a future Phase II application, which would also include more thorough assessment of the compounds' safety in vitro and in vivo. Our long- term goal is to advance the lead compound into clinical testing for the treatment of AKI.